Beryllium sensitization and chronic beryllium disease (CBD) continue to affect individuals who have occupational or environmental exposure, especially those with genetic susceptibility. The long-term objectives of this Program Project Grant are to evaluate the basic immune and inflammatory mechanisms underlying beryllium sensitization and chronic beryllium disease, and to establish the relationship between beryllium exposure and immunogenetics. The proposal consists of four projects and three core units. Project 1 will determine the mechanisms by which beryllium induces aberrant, high production of the pro- inflammatory cytokine tumor necrosis factor-alpha in CBD, focusing on the priming effects of interferon-gamma and direct effects of beryllium sensitization, in the progression from sensitization to CBD, and in the development of severe forms of this granulomatous disorder. Project 3 will determine the role of beryllium-reactive CD4+ T cells and the affinity of the T cell antigen receptor for the beryllium/peptide/major histocompatibility (MHC) complex. In doing so, this project will determine qualitative and quantitative differences in T cell recognition of beryllium, in the ability of beryllium-specific CD4+ T cells to secrete pro-inflammatory cytokines, utilizing this information to develop biomarkers of disease progression. Project 4 will determine the role of oxidative stress in enhancing the antigen presenting cell's ability to present beryllium antigen to T cells. It will test the hypothesis that beryllium induces oxidative stress which promotes an excessive cytokine response and T cell proliferation in CBD. The overall rationale for the Program Project is to use an interdisciplinary approach to define the genetic underpinnings of the cellular response to beryllium, to relative mechanisms to human exposure risk factors, and develop new biological markers of CBD risk, disease progression, and prognosis.